Cooling Anesthesia for Intravitreal Injection: Results of the Prospective Open-Label, Dose-Ranging COOL-1 Trial

Abstract Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, with inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D supplementation, which can lead to or exacerbate hypercalciuria. As a result, patients may develop nephrolithiasis and/or nephrocalcinosis, which can progress to renal insufficiency. Calcilytics (antagonists of the CaSR) have demonstrated in in vitro and in vivo models of ADH1, as well as in a small clinical trial (Roberts et al, JBMR 2019), the ability to shift the dose-response relationship between extracellular calcium and the cellular response of cells bearing the mutant CaSR towards normal. This shift has the potential to increase endogenous PTH secretion which in turn may promote skeletal release of calcium into the bloodstream, production of endogenous calcitriol, renal excretion of phosphate, and renal reabsorption of calcium. Additionally, direct effects of calcilytics on renal CaSRs may further reduce renal calcium and magnesium excretion in ADH1. Taken together, this class of drugs has the capacity to restore normal mineral homeostasis, without calcium and activated vitamin D supplements and without attendant risks of iatrogenic hypercalciuria. This Phase 2b, open-label, dose-ranging study will evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of the calcilytic encaleret (CLTX-305) in up to 16 participants with ADH1 (NCT04581629). The study will consist of 3 periods. In periods 1 and 2, participants will undergo a 1-week inpatient evaluation to study the safety and tolerability of daily and twice-daily doses of encaleret. Period 3 will follow participants for up to 24 weeks of continuous outpatient dosing, with periodic inpatient and outpatient assessments. The primary endpoint of period 3 is the change from baseline in albumin-corrected blood calcium concentration. Secondary endpoints of the study include the change in urine calcium (fractional and 24-hour excretion), 1,25-dihydroxy-Vitamin D, phosphate, magnesium, and other blood/urine biomarkers. Enrollment for this study at the National Institutes of Health (NIH) began in September 2020 with topline results expected in 2021. This study is supported by Calcilytix Therapeutics, Inc. and the NIH Intramural Research Program.

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The Effects of Encaleret (CLTX-305) on Mineral Physiology in Autosomal Dominant Hypocalcemia Type 1 (ADH1) Demonstrate Proof-of-Concept: Early Results From an Ongoing Phase 2b, Open-Label, Dose-Ranging Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.545 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A269-A269

Author(s):

Rachel Ilana Gafni ◽

Iris Ruth Hartley ◽

Kelly Lauter Roszko ◽

Edward F Nemeth ◽

Karen A Pozo ◽

...

Keyword(s):

Conventional Therapy ◽

Autosomal Dominant ◽

Proof Of Concept ◽

Open Label ◽

In Vivo Models ◽

Blood Calcium ◽

Label Dose ◽

Dose Ranging ◽

Autosomal Dominant Hypocalcemia

Abstract Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene (CASR) encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D, targeting blood calcium at or slightly below the low-normal level to minimize hypocalcemic symptoms. This supplementation typically causes or exacerbates hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. It has been demonstrated in in vitro and in vivo models of ADH1, as well as in a Phase 2b clinical study (Roberts et al, JBMR 2019) that calcilytics (negative allosteric modulators of the CaSR), have the ability to shift the concentration-response relationship between extracellular calcium and the mutant CaSR towards normal. Six adults with ADH1 due to four distinct activating variants of the CASR were studied in an ongoing, three period, Phase 2b, open-label, dose-ranging study [NCT04581629] of the calcilytic encaleret (CLTX-305). Calcium, magnesium, and calcitriol supplements were discontinued at the start of Period 1, and subjects received sequential, increasing daily doses of encaleret for 3d (30 mg, 90 mg, 180 mg) followed by 120 or 180 mg twice daily on day 4 and 5, while undergoing frequent blood and urine sampling. The mean baseline PTH was 3.4 ± 4.5 pg/mL (mean ± SD; nl 10–65); on encaleret, there was a rapid, dose-dependent increase in PTH to a mean level of 64.8 ± 49.6 pg/mL over 24 hours by day 5. Albumin-corrected blood calcium (cCa) increased from a baseline of 7.6 ± 0.6 mg/dL (nl 8.4–10.2) to a 24-hour mean on day 5 of 9.0 ± 0.5 mg/dL. Phosphorus decreased from a baseline of 4.5 ± 0.7 mg/dL (nl 2.3–4.7) to a 24-hour day 5 mean of 2.9 ± 0.5 mg/dL. Magnesium increased from a baseline of 1.6 ± 0.4 mg/dL (nl 1.6–2.6) to a 24-hour day 5 mean of 2.0 ± 0.5 mg/dL. Blood calcium, phosphorus and magnesium were mostly maintained within the normal range in ADH1 subjects by days 4 and 5. Twenty-four hour urine calcium was elevated at the screening visit while subjects were on conventional therapy (436 ± 255 mg/day, nl < 250–300) and decreased with increasing doses of encaleret to 63 ± 127 mg/day on day 5. Urinary calcium excretion became normal in 3 subjects and undetectable in 3 subjects while on encaleret. Encaleret was well-tolerated, with no serious adverse events reported. The consistent mineral responses following encaleret administration in all six ADH1 subjects with four distinct CASR genotypes represents preliminary proof-of-concept that encaleret may be an efficacious treatment for ADH1. The longer-term evaluation of encaleret in ADH1 subjects is ongoing.

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